The prenatal and early postnatal environments are increasingly recognized as important determinants of chronic disease risk. Low birth weight (LBW) is associated with increased risk of diabetes and cardiovascular disease. Altered body composition with increased fat mass is a key contributor to these risks, yet accelerated postnatal adipose tissue growth following prenatal undernutrition is not well understood. The mentor has developed a mouse model of prenatal undernutrition. Food restriction during pregnancy of F0 females causes LBW, increased fat mass, and diabetes in F1 offspring. Prenatally undernourished F1 mice have significant reductions in adipose tissue expression of Pref1, an imprinted gene that is a critical negative regulator of adipogenesis. Furthermore, reductions in Pref1 and obesity risk are transmitted intergenerationally, despite no nutritional manipulation in the F2 generation, raising the possibility of epigenetic regulation. The overarching goal of this proposal is to examine how Pref1 expression contributes to obesity risk following prenatal undernutrition, and to determine whether manipulation of adipose tissue Pref1 expression via genetic or pharmacologic approaches modulates this risk. In Aim 1, we will dissect the relative contribution of changes within F1 germ cells vs. effects of the F1 intrauterine environment in the inter- generational transmission of obesity and Pref1 expression by using embryo transfer techniques. In addition, we will look for similarities between F0 and F1 gestational environments through a metabolomic approach. In Aim 2, we will test whether Pref1 expression directly contributes to obesity risk following prenatal undernutrition by imposing our F0 prenatal food restriction protocol on transgenic mice with overexpression of Pref1. We hypothesize that Pref1 overexpression will prevent the development of obesity and diabetes in prenatally undernourished F1 offspring. Finally, in Aim 3, we will test whether treatment with a growth hormone releasing analog can (a) modulate Pref1 expression in vivo and (b) improve body composition in prenatally undernourished F1 mice. These experiments are novel in that they combine genetic and physiologic approaches to examine the regulation of excessive adipose tissue growth following LBW. These data will be used toward the development of biomarkers of adverse prenatal environments and targeted preventive strategies. PUBLIC HEALTH RELEVANCE: Prenatal under nutrition can increase risk of diabetes and abdominal obesity. These studies will examine the causes of obesity in our mouse model of prenatal undernutrition. We will determine how a specific gene, Pref1, is altered, and test whether increasing Pref1 expression genetically or pharmacologically can prevent obesity.